DNA/RNA material contained in circulating extracellular vesicles secreted into the blood stream by tumor cells may capture cancer genomics and transcriptomic evolution in patients with metastatic prostate cancer, according to a recent study published by Casanova et al in Cancer Cell.
Background
Prostate cancer was the second leading cancer type and the fifth leading cause of cancer-related mortality among men in 2022. The disease has an estimated 1.5 million new cases and 397,000 deaths globally. Mortality rates have decreased in most high income-countries since the mid-1990s—likely reflecting advancements in treatments and early detection. The majority of patients diagnosed with early-stage prostate cancer can be cured through cancer surgery, radiotherapy, or brachytherapy with or without hormone therapy.
Although novel systemic therapies, hormone-based treatments, and chemotherapy have improved the survival of patients with metastatic prostate cancer, treatment responses are highly heterogeneous and many tumors eventually develop drug resistance.
“The development of new tools and the identification of novel biomarkers of response and resistance are key to guiding and adapting treatment strategies based on the monitoring of tumor evolution in individual patients,” suggested senior study author Joaquin Mateo, MD, PhD, Head of the Vall d’Hebron Institute of Oncology’s Prostate Cancer Translational Research Group and a medical oncologist at the Vall d’Hebron University Hospital at the Vall d’Hebron Campus.
Under normal conditions, extracellular vesicles are conduits of intercellular communication and mediators of various biological processes. These heterogeneous particles contain proteins, lipids, metabolites, RNA, and DNA as cargo. Extracellular vesicles produced by tumor cells promote cancer cell communication and their protein load composition plays a key role in tumor progression, immune regulation, and metastasis.
“However, the potential of tumor extracellular vesicles as a source of clinically relevant DNA and RNA biomarkers remains largely unexplored. We have now developed a new liquid biopsy application for the analysis of circulating vesicles secreted by cancer cells and performed multiomic profiling for the genomic and transcriptomic characterization of these tumors,” explained lead study author Irene Casanova, PhD, an associate investigator of the Vall d’Hebron Institute of Oncology’s Prostate Cancer Translational Research Group.
Study Methods and Results
In the recent study, the researchers analyzed liquid biopsies collected via plasma series sampling throughout the course of disease among 53 patients with metastatic castration-resistant prostate cancer who received hormone therapy or chemotherapy. They then examined the DNA and RNA in circulating extracellular vesicles to confirm that the vesicles contained tumor-derived genetic material that may help to identify specific mutations present in tumor cells and forecast the disease evolution.
Using a newly developed liquid biopsy technique, the researchers demonstrated that the DNA and RNA contained in circulating vesicles reflected the genomic and transcriptomic features in metastatic prostate cancer. Further, mRNA expression analysis—performed in extracellular vesicles in liquid biopsies—enabled the monitoring of on-therapy changes in the tumors.
Conclusions
“The study of transcriptomic features by liquid biopsy in clinical samples has mostly been unsuccessful due to the rapid degradation of RNA when it is not shielded by the cell membrane. Our study shows that tumor mRNA encapsulated in circulating extracellular vesicles is protected and therefore represents a promising source of clinically relevant information,” Dr. Casanova underscored.
The researchers characterized the transcriptomic profile of the prostate tumors that could potentially serve as a biomarker of response or resistance to therapy. Their findings could also expand the opportunities to explore cancer from minimally invasive liquid biopsies.
“Our findings open avenues for biomarkers of therapy response and acquired drug resistance to help guide clinical decisions in individual patients with metastatic prostate cancer throughout the course of disease,” highlighted Dr. Mateo. “Drug resistance remains a major challenge in more effectively treating cancer. Adaptive mechanisms of resistance occur more rapidly and dynamically than mutations driving acquired resistance. Monitoring these changes as they occur by liquid biopsy will enable real‐time clinical decision‐making and the selection of adaptive treatments to help combat evolving tumor dynamics earlier,” he concluded.
Disclosure: This study was funded in part by a ”la Caixa” Foundation Junior Leader Fellowship, the FERO Foundation, the Ramon Areces Foundation, and the CRIS Cancer Foundation. For full disclosures of the study authors, visit cell.com.
